The most pertinent prior art reference vis-a-vis benzodiazepines is U.S. Pat. No. 4,229,447 to Porter which discloses a method of administering certain benzodiazepines sublingually and buccally. Porter specifically mentions the sublingual or buccal administration of diazepam, lorazepam, oxazepam, temazepam and chlorodiazepoxide and describes two generic structures of benzodiazepines that may be administered sublingually or buccally. The compound shown below is contemplated by the generic structures in Porter. All of the benzodiazepines disclosed and the generic structure described in Porter are BZ.sub.1 -BZ.sub.2 receptor non-specific since they lack the trifluoro ethyl group in the N position of the "B" ring which confers BZ.sub.1 specificity. ##STR1##
The method of Porter is based on the rapid buccal or sublingual absorption of selected benzodiazepines to attain effective plasma concentration more rapidly than oral administration. In contrast, while parenteral administration provides a rapid rise of blood levels of the benzodiazepines, parenteral administration is frequently accompanied by pain and irritation at the injection site and may require sterilization of the preparatives and the hypodermic syringes.
Porter points out that the intraoral, i.e. buccal or sublingual administration, of lipid soluble benzodiazepines results in therapeutic levels resembling parenteral administration without some of the problems associated therewith. The administration technique of Porter for benzodiazepines in general builds on a long established knowledge in pharmacology that drugs absorbed in the intraoral route give rise to more rapid absorption than when swallowed into the stomach. What is not recognized by Porter, however, are concerns with first-pass metabolism which can be avoided either with the sublingual or parenteral route of drug administration of certain benzodiazepines.
Porter does not recognize that first-pass metabolism designates the drug absorption directly into the portal blood supply leading to the liver and that the liver in turn rapidly absorbs and metabolizes the drug with its first-pass high concentration through the liver blood supply. Thus, large amounts of the drug may never be seen by the systemic circulation or drug effect site. Porter further does not recognize that the more rapid metabolism via the first-pass metabolism route can lead to accelerated dealkylation with formation of high plasma concentrations of an unwanted metabolite. Thus, applicants' concern with avoiding the degradation of the parent compound and its desired positive effect and the metabolism thereof to an undesired metabolite is neither recognized nor addressed by Porter, which only addresses the ability of the oral mucous membranes to absorb certain benzodiazepines fast and achieve high plasma levels thereof quickly.
The specific drug for which this phenomenon was demonstrated by Porter was lorazepam which has a simple metabolism that results in it not being metabolized to active compounds. Also, and very significantly, the issue of human nervous system receptor specificity and activation for BZ.sub.1 and BZ.sub.2 type receptors is not recognized by Porter either generally or with reference specifically to trifluorobenzodiazepines.
U.S. Pat. No. 3,694,552 to Hester discloses that 3-(5-phenyl-3H-1,4-benzodiazepine-2-yl) carbazic acid alkyl esters, which are useful as sedatives, hypnotics, tranquilizers, muscle relaxants and anticonvulsants, can be administered sublingually. Subsequently issued U.S. Pat. No. 4,444,781 to Hester specifically teaches that 8-chloro-1-methanol-6-(o-chlorophenyl)-4H-s-triazolo 4,3-a! 1,4!-benzodiaz epine therapeutic compounds, which are useful as soporifics, can be suitably prepared for sublingual use.
Also, U.S. Pat. No. 4,009,271 to vonBebenburg et al. discloses that 6-aza-3H-1,4-benzodiazepines and 6-aza-1,2-dihydro-3H-1,4-benzodiazepines (which have pharmacodynamic properties including psychosedative and anxiolytic properties as well as antiphlogistic properties) can be administered enterally, parenterally, orally or perlingually.
The chemical formula of nefazodone is 2-(3-(-4-(3-chlorophenyl)-1-piperazinyl)propyl)-5-ethyl-2,4-dihydro-4-(2-p henoxyethyl)-)3H-1,2,4-triazol-3-one hydrochloride.
Patients with obsessive compulsive disorder respond to meta-chlorophenylpiperazine (hereinafter, abbreviated as mCPP), an undesirable metabolite of nefazodone, by becoming much more anxious and obsessional as reported by Zohar et al., in "Serotonergic Responsivity in Obsessive Compulsive Disorder: Comparison of Patients and Healthy Controls", Arch Gen. Psychiatry, Vol 44, pp 946-951 (1987). The peak in the anxiousness and obsessional behaviors is observed within three hours of mCPP administration and the duration of the worsening ranges from several hours to as much as 48 hours. Much more significantly, mCPP induced a high rate of emergence of entirely new obsessions or the reoccurrence of obsessions that had not been present in the patients for several months. Patients also reported being more depressed and dysphoric. Zohar et al. administered 0.5 mg/kg of mCPP orally to subjects in eliciting their obsessional symptoms. The peak plasma concentration in the control patients was 33.4.+-.17.34 ng/ml, whereas, in the obsessional patients, the peak plasma concentration inducing the obsessional behavior was 26.9 ng/ml.+-.12.33.
Hollander et al., in "Serotonergic Noradrenergic Sensitivity in Obsessive compulsive Disorder: Behavioral Findings", Am J Psychiatry, Vol 1945, pp 1015-1017 (1988), also have reported many of these obsessional worsening effects in obsessive compulsive patients.
Additionally, Kahn et al., in "Behavioral Indications for Serotonin Receptor Hypersensitivity in Panic Disorder", Psychiatry Res., Vol 25, pp 101-104 (1988), have reported mCPP induces anxiety in a group of panic disorder patients.
Walsh et al., as reported in "Neuroendocrine and Temperature Effects of Nefazodone in Healthy Volunteers", Biol. Psychiatry, Vol. 33, pp. 115-119 (1993), administered oral doses of 50 mg and 100 mg of nefazodone to normal subjects and measured nefazodone and its metabolite mCPP. For the 50 mg dose, the nefazodone/mCPP area under the curve (hereinafter, abbreviated as AUC) ratio was 1.58. For the 100 mg dose, the AUC ratio was 1.63, indicating that within the first 3 hours, nefazodone is substantially metabolized to mCPP at levels considerably above the mCPP levels that Zohar et al. found to induce anxiety and obsessional states in susceptible individuals.
In studies in dogs, intravenous dosing of nefazodone reduced plasma mCPP Cmax by 50% from that found with oral dosing, as reported by Shukla et al., "Pharmacokinetics, Absolute Bioavailability, and Disposition of .sup.14 C! Nefazodone in the Dog", Drug Metab Disposition, Vol 21, No. 3, pp. 502-507 (1993).